This is a continuation of a project, for which the long-term goal is to define T cell effector mechanisms at the level of the small intestinal epithelium, by characterizing the stimulatory and costimulatory signals that drive intestinal intraepithelial lymphocytes (lELs) through activation. The central hypothesis for these studies is that small intestinal lELs are partially-activated T cells that can be rapidly driven to express additional effector activities through an ordered process of costimulatory activation, and that the nature and magnitude of the effector responses generated are the direct consequence of those activation signals. There are four integrated Specific Aims. Aim 1: To characterize the costimulatory effects of CD43 S7+ and S7- lELs with regard to apoptosis, death-proneness, and activation-induced cell death; to define the role of CD43 on IEL proliferation in vivo. Aim 2: To characterize the secondary costimulatory effects of Ly-6C and OX40 on IEL proliferation and cytokine activity: to determine the role of immune (CD3 signaling) vs. non-immune (IFN-alpha) induction of Ly-6C on IEL proliferative activities. Aim 3: To use small selective gene and protein array panels of T cell immunoregulatory response molecules to map the appearance of immune-activating cytokines and chemokines in lELs as they proceed from the partially activated stage into intermediated and fully activated stages. Aim 4: To use small selective gene and protein array panels of T cell immunoregulatory response molecules to identify inflammatory and immunoregulatory cytokines and chemokines in lELs from SAMP1/YitFc mice prior to and after the development of chronic small intestinal inflammation in order to identify important immunoregulatory response molecules and costimulatory signals that are linked to intestinal inflammation; to initiate intervention therapy in SAMP1/YitFc mice based on findings from studies in Specific Aims 1, 2, and 3. These studies will provide important new information about the cellular and molecular events that regulate IEL activation, and will have direct implications for understanding intestinal T cells during infection, cancer, and autoimmunity.